Dataset Information

Pharmacokinetics and pharmacodynamic effect of crenezumab on plasma and cerebrospinal fluid beta-amyloid in patients with mild-to-moderate Alzheimer's disease.

ABSTRACT: BACKGROUND:Crenezumab, a fully humanized anti-beta-amyloid (A?) immunoglobulin G4 (IgG4) monoclonal antibody, binds to both monomeric and aggregated forms of A?. We assessed the pharmacokinetics (PK)/pharmacodynamics (PD) of crenezumab and its interaction with monomeric A?(1-40) and A?(1-42) peptides in serum/plasma and cerebrospinal fluid (CSF) samples from the phase II ABBY and BLAZE studies and the phase Ib GN29632 study. METHODS:In ABBY, BLAZE, and GN29632 studies, patients with mild-to-moderate AD were treated with either placebo or crenezumab (300?mg subcutaneously every 2?weeks [q2w], or 15?mg/kg, 30?mg/kg, 45?mg/kg, 60?mg/kg, or 120?mg/kg intravenously q4w). Serum/plasma PK/PD analyses included samples from 131 patients who received crenezumab in all three studies. CSF PK/PD analyses included samples from 76 patients who received crenezumab in ABBY or BLAZE. The impact of baseline patient factors on A? profiles was also evaluated. RESULTS:The serum concentration of crenezumab increased in a dose-proportional manner between 15 and 120?mg/kg q4w. Total monomeric plasma A?(1-40) and A?(1-42) levels significantly increased after crenezumab administration. The mean crenezumab CSF to serum ratio was ~?0.3% and was similar across dosing cohorts/routes of administration. No clear correlation was observed between crenezumab concentration and A?(1-42) increase in CSF at week 69. The target-mediated drug disposition (TMDD) model described the observed plasma concentration-time profiles of crenezumab and A? well. Elimination clearance (CLel) and central volume of distribution (Vcent) of crenezumab were estimated at 0.159?L/day and 2.89?L, respectively, corresponding to a half-life of ~?20?days. Subcutaneous bioavailability was estimated at 66.2%. CONCLUSIONS:Crenezumab PK was dose proportional up to 120?mg/kg, with a half-life consistent with IgG monoclonal antibodies. Our findings provide evidence for peripheral target engagement in patients with mild-to-moderate AD. The study also showed that a model-based approach is useful in making inference on PK/PD relationship with unmeasured species such as free plasma A? levels. TRIAL REGISTRATIONS:ABBY: ClinicalTrials.gov, NCT01343966. Registered April 28, 2011. BLAZE:ClinicalTrials.gov, NCT01397578. Registered July 19, 2011. GN29632: ClinicalTrials.gov, NCT02353598. Registered February 3, 2015.

SUBMITTER: Yoshida K

PROVIDER: S-EPMC6977279 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Pharmacokinetics and pharmacodynamic effect of crenezumab on plasma and cerebrospinal fluid beta-amyloid in patients with mild-to-moderate Alzheimer's disease.

Yoshida Kenta K Moein Anita A Bittner Tobias T Ostrowitzki Susanne S Lin Helen H Honigberg Lee L Jin Jin Y JY Quartino Angelica A

Alzheimer's research & therapy 20200122 1

<h4>Background</h4>Crenezumab, a fully humanized anti-beta-amyloid (Aβ) immunoglobulin G4 (IgG4) monoclonal antibody, binds to both monomeric and aggregated forms of Aβ. We assessed the pharmacokinetics (PK)/pharmacodynamics (PD) of crenezumab and its interaction with monomeric Aβ(1-40) and Aβ(1-42) peptides in serum/plasma and cerebrospinal fluid (CSF) samples from the phase II ABBY and BLAZE studies and the phase Ib GN29632 study.<h4>Methods</h4>In ABBY, BLAZE, and GN29632 studies, patients wi ...[more]

PMID: 31969177

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Project description:BACKGROUND:We investigated the effect of crenezumab, a humanized anti-amyloid-beta (A?) immunoglobulin (Ig)G4 monoclonal antibody, on biomarkers of amyloid pathology, neurodegeneration, and disease progression in patients with mild-to-moderate Alzheimer's disease (AD). METHODS:This double-blind, placebo-controlled, randomized phase II study enrolled patients with mild-to-moderate AD and a Mini-Mental State Examination (MMSE) score of 18-26. In part 1 of the study, patients were 2:1 randomized to receive low-dose subcutaneous (SC) 300 mg crenezumab every 2 weeks (q2w) or placebo for 68 weeks; in part 2, patients were 2:1 randomized to receive high-dose intravenous (IV) 15 mg/kg crenezumab every 4 weeks (q4w) or placebo for 68 weeks. The primary endpoint was change in amyloid burden from baseline to week 69 assessed by florbetapir positron emission tomography (PET) in the modified intent-to-treat population. Secondary endpoints were change from baseline to week 69 in cerebrospinal fluid (CSF) biomarkers and fluorodeoxyglucose PET, and change from baseline to week 73 in 12-point Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-Cog12) and Clinical Dementia Rating Sum of Boxes (CDR-SB). Safety was assessed in patients who received at least one dose of study treatment. RESULTS:From August 2011 to September 2012, 91 patients were enrolled and randomized (low-dose SC cohort: crenezumab (n?=?26) or placebo (n?=?13); high-dose IV cohort: crenezumab (n?=?36) or placebo (n?=?16)). The primary endpoint was not met using a prespecified cerebellar reference region to calculate standard uptake value ratios (SUVRs) from florbetapir PET. Exploratory analyses using subcortical white matter reference regions showed nonsignificant trends toward slower accumulation of plaque amyloid in the high-dose IV cohort. In both cohorts, a significant mean increase from baseline in CSF A?(1-42) levels versus placebo was observed. Nonsignificant trends toward ADAS-Cog12 and CDR-SB benefits were identified in a mild (MMSE 20-26) subset of the high-dose IV cohort. No amyloid-related imaging abnormalities due to edema/effusion were observed. CONCLUSION:The primary endpoint was not met. Exploratory findings suggest potential A? target engagement with crenezumab and possible slower accumulation of plaque amyloid. Studies investigating the effects of higher doses of crenezumab on amyloid load and disease progression are ongoing. TRIAL REGISTRATION:ClinicalTrials.gov, NCT01397578 . Registered on 18 July 2011.

Dataset Information

Pharmacokinetics and pharmacodynamic effect of crenezumab on plasma and cerebrospinal fluid beta-amyloid in patients with mild-to-moderate Alzheimer's disease.

Publications

Pharmacokinetics and pharmacodynamic effect of crenezumab on plasma and cerebrospinal fluid beta-amyloid in patients with mild-to-moderate Alzheimer's disease.

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